Knockdown of interleukin-10 induces the redistribution of sigma1-receptor and increases the glutamate-dependent NADPH-oxidase activity in mouse brain neurons

BACKGROUND: In the central nervous system, interleukin-10 (IL-10) provides trophic and survival effects directly on neurons, modulates neurite plasticity, and has a pivotal importance in the neuronal regeneration in neurodegenerative and neuroinflammatory conditions. This cytokine is primarily produced by glial cells and has beneficial effects on the neuronal viability. However, the mechanisms of IL-10-elicited neuroprotection are not clear. RESULTS: Membrane preparations, isolated from wild-type (Wt) and IL-10 knockout (KO) mice brain were used in this study. It has been shown that compared to wild-type mice, in IL-10 KO mice brain, the amount of immunoglobulin binding protein (BiP) is greatly increased, whereas the content of sigma receptor-1 (SigR1) is not changed significantly. Co-immunoprecipitation experiments have shown that the association of SigR1 with small GTPase Rac1 (Ras-related C3 botulinum toxin substrate 1), NR2B subunit of NMDA-receptor (NMDAR) and inositol-3-phosphate receptor (IP3R) is higher in the IL-10 KO mice brain than in the Wt mice brain. Besides, we have found that either glutamate or sigma ligands, separately or together, do not change glutamate-induced NADPH-oxidase (NOX) activity in Wt-type mice brain membrane preparations, whereas in IL-10 KO mice high concentration of glutamate markedly increases the NOX-dependent production of reactive oxygen species (ROS). Glutamate-dependent ROS production was decreased to the normal levels by the action of sigma-agonists. CONCLUSIONS: It has been concluded that IL-10 deprivation, at least in part, can lead to the induction of ER-stress, which causes BiP expression and SigR1 redistribution between components of endoplasmic reticulum (ER) and plasma membrane. Moreover, IL-10 deficiency can change the specific organization of NMDAR, increasing the surface expression of SigR1-sensitive NR2B-containing NMDAR. In these conditions, glutamate-dependent ROS production is greatly increased leading to the initiation of apoptosis. In this circumstances, sigma-ligands could play a preventive role against NMDA receptor-mediated excitotoxicity.

Receptores sigma1: um novo alvo para o tratamento farmacológico da depressão? / A new target for the pharmacologycal treatment of depression?

Apesar de décadas de estudos sobre os antidepressivos (ADs), seus mecanismos de ação permanecem obscuros. Muitos ADs interagem com receptores sigma e evidências crescentes sugerem que estas proteínas medeiam efeitos antidepressivos em animais e humanos. Os receptores sigma são subdivididos em dois subtipos, sigma-1 e sigma-2. Em particular, uma potencial atividade antidepressiva foi postulada para agonistas do receptor sigma-1, os quais se localizam predominantemente no reticulo- endoplasmático de neurônios e oligodendrócitos. Os receptores sigma estão localizados em regiões cerebrais que são afetadas na depressão e são capazes de modular a atividade dos sistemas centrais de neurotransmissores, incluindo os sistemas noradrenérgico, serotonérgico, dopaminérgico e glutamatérgico (NMDA), que são considerados importantes no mecanismo de ação dos ADs conhecidos. O foco desta revisão é discutir a literatura relacionada aos receptores sigma e aos seus ligantes em relação às suas propriedades antidepressivas.